Nivolumab Plus Ipilimumab Shows Long-Term Survival in Patients With Advanced Melanoma


In an interview with <em>Targeted Oncology</em>, Michael Atkins, MD, discussed the latest follow-up data from the combination of nivolumab and ipilimumab across 2 trials and next steps in the research with this combination for patients with advanced melanoma.

Michael Atkins, MD

Michael Atkins, MD

Michael Atkins, MD

Long-term follow-up results from CA209-004, a phase I study analyzing patients with advanced, unresectable melanoma treated with nivolumab (Opdivo) plus ipilimumab (Yervoy), showed favorable survival outcomes at the 5-year mark.

For the analysis, patients who were previously treated or untreated were enrolled and separated into5 cohorts. Each cohort received different doses of nivolumab and ipilimumab. The survival exploratory endpoint was analyzed for 3 years, while the primary and secondary endpoints of safety, response, and progression-free survival, were followed for 2.5 years.

The median follow-up was 43.1 months across all 4 cohorts (n = 94), at 4 years or longer. At both 4 years and 4.5 years, the overall survival (OS) rate was 57% (95% CI, 47%-67%). The was a difference in OS in patients with a normal lactate dehydrogenase (LDH; 62%) versus those with an elevated LDH (49%). OS also differed based on the presence of a gene mutation. Patients withBRAF-mutated tumors showed a 4-year OS rate of 61%, while those withBRAFwild-type tumors showed an OS rate of 54%.1

These results come after multiple reports that the combination of nivolumab and ipilimumab is active,2safe and effective,3and helps maintain the quality of life4in patients with melanoma.

In an interview withTargeted Oncology, Michael Atkins, MD, deputy director, Georgetown Lombardi Comprehensive Cancer Center, discusses the latest follow-up data from the combination of nivolumab and ipilimumab across 2 trials and next steps in the research with this combination for patients with advanced melanoma.

TARGETED ONCOLOGY: Can you discuss the CA209-004 trial and data that have been reported to date?

Atkins: This is the first phase I trial combining checkpoint inhibitors against CTLA-4 and anti—PD-1, specifically ipilimumab and nivolumab. It was done in patients with melanoma. It looks at 5 different concurrent dosing cohorts with various schedules of&nbsp;ipilimumab and nivolumab over a period of a maximum of 2 years. It was originally reported out at ASCO 2013 and published in theNew England JournalofMedicineshowing a remarkable response rate of 53% and rapid, quick responses. This led to randomized phase II and randomized phase III trials comparing the combination to single-agent&nbsp;ipilimumab or ipilimumab and&nbsp;nivolumab.&nbsp;

It ultimately led to the approval of this combination as a preferred treatment for patients with metastatic melanoma. At ASCO 2019, we reported on the long-term follow-up of how these first patients treated with ipilimumab and nivolumab have done. We previously reported out the 3-year overall survival of patients on this study and we reported that 63% of patients were alive at 3 years and the median overall survival was in the 22-month range.&nbsp;

We are now reporting the final overall survival with a minimum follow-up of 5 years and also reporting what has happened to patients after they stopped treatment.

TARGETED ONCOLOGY: What were the findings of the CA209-004 trial?

Atkins: What we found was that 57% of patients were alive at 4 years. There was favorable survival of at least 49% in every cohort of patients that we examined. [This was true] whether it wasBRAF-mutant, orBRAFwild-type, PD-L1 positive or PD-L1 negative, and regardless of the stage, LDH, and whether or not patients had&nbsp;received&nbsp;prior therapy. At least 49% of patients in that group and as many as 71% of patients were alive at 4 years. That was the major endpoint that a lot of patients, no matter how risky their tumor was, as many as half are going to appear to be cured of their disease by these combination regimens.

The second thing that we reported was that [86% of the patients] who stopped treatment because they had completed therapy were still alive for 2 to 3 years after they stopped treatment. For patients who stopped treatment because of toxicity, 70% of those patients were still alive. Once again, [a patient's risk] didn't matter if they made it into those categories but [patients] were more likely to complete treatment if they had a normal LDH, if their tumor wasBRAFwild-type, and if you hadn't received prior treatment.&nbsp;

The quality of life for those patients who have finished treatment, whether they had received toxicity or not is wonderful. We have turned melanoma, which is a devastating disease, into one that is curable in the majority of patients. And the patients that are living off treatment are not just surviving, they're thriving.

TARGETED ONCOLOGY: What were some of the toxicities that led to discontinuation of treatment in this study?

Atkins: The toxicities that led to discontinuation are the ones that have been well described with this combination. These are immune-related adverse events which are exacerbated when your put ipilimumab and an anti—PD-1 together. They include skin rash, fatigue, thyroid problems,&nbsp;colitis, liver function test abnormalities, and a variety of other less common immune-related adverse events.&nbsp;

The important point is that the toxicity can be managed and controlled, and patients can either complete therapy or stop treatment because of toxicity and at least 70% of those patients will be alive long-term.

TARGETED ONCOLOGY:Can provide an overview of the CheckMate 204 trial what was found prior to this year&rsquo;s ASCO Annual Meeting?

Atkins: Checkmate 204 extended the experience with the combination of ipilimumab and nivolumab to patients who have activated brain metastases. There were 2 cohorts of patients that were enrolled in the trial. One was a large cohort of patients who had asymptomatic brain metastases, which represented about 100 patients in the trial. The second cohort was of patients who had asymptomatic brain&nbsp;metastases who either were on low doses of steroids or had just come off of steroid treatment. That represented about 18 patients.&nbsp;

The asymptomatic cohort was presented previously and published in theNew England Journal of Medicinein December 2018, showing a 55% response rate in the brain, which was equivalent to the response rate systemically. So, when it comes to immune therapy, there is no blood-brain barrier. The active immune cells can get into the brain and control the disease in the brain as well as the systemic disease. There was a higher percentage of complete responses in the brain than there were systemically. When it was first reported, it was early. Most of those responses were ongoing and there were no treatment-related toxicities that were new and none that were related to CNS.

What was reported this time is a longer follow-up on those 101 patients with asymptomatic brain metastases and for the first time, data on the activity in the 18 patients with symptomatic brain metastases.

The longer follow-up shows that 73% of patients with asymptomatic brain metastases are alive at 18 months and it looks like that is going to be a tail on the survival curve. Fifty-five percent of patients are responding and 87% of those responses are ongoing, meaning that these are likely to be durable responses, similar to what we've seen with systemic disease.

With the symptomatic cohort, the data were not as promising. Of the 18 patients, there were 4 responses, 2 complete responses, and 2 partial responses for a 22% response rate. Two of those 4 responses are ongoing. All of those 4 patients who responded in the CNS also had a systemic response, so these were not artifactual CNS responses. Most of the patients had trouble getting in more than 1 dose of therapy because of swelling in the brain, needing to increase the dose of steroids or other problems. For most patients with symptomatic brain metastases, we need to look at developing other strategies than just giving them ipilimumab and nivolumab.

TARGETED ONCOLOGY: Are there any next steps to this research?

Atkins: Next steps to this research are to continue to follow these patients to see how they do once treatment is stopped. Also [we have] to think about ways in which we can potentially reduce the swelling in the brain or [better prepare patients with symptomatic brain metastases better for immunotherapy]. [We could do things] such as local therapy to resect large metastases or targeted radiation therapy to get patient off steroids before we treat them and give things that control the edema in the brain, like bevacizumab (Avastin) or other treatments. [These] might allow for patients to get more therapy and more activity of the immune system in the brain before that start having symptoms because of swelling in the enclosed space, which is inside of the skull.


  1. Atkins MA, Kirkwood JM, Wolchok JD, et al. Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma. J Clin Oncol. 2019;37(suppl; abstr 9533).
  2. Wolchok JD, Sileni VC, Gonzalez R, et al. Updated results from a phase III trial of nivolumab (NIVO) combined with ipilimumab (IPI) in treatment-naive patients (pts) with advanced melanoma (MEL) (CheckMate 067). J Clin Oncol. 2016;34(suppl; abstr 9505)
  3. Tawbi Ha,Forsynth PA, Algazi A, et al. Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain. N Engl J Med 2018; 379:722-730. DOI: 10.1056/NEJMoa1805453.
  4. Schadendorf D, Larkin JM, Wolchok Jd, et al. Patient-reported quality of life (QoL) of advanced melanoma patients in a Phase 3 study of nivolumab (NIVO) with or without ipilimumab (IPI) versus IPI: CheckMate 067 4-year data. J Clin Oncol. 2019;37(suppl; abstr 9551).
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